The present invention relates to the interaction between vMIP-I and CCR8 receptor and the use of these molecules as well as agonists and antagonists thereof in modulating Th1 balance and the immune response.
The chemokines are a sub-family of chemoattractant cytokines that were classically characterized by their ability to mediate leukocyte trafficking by binding to specific G-protein linked seven transmembrane spanning receptors, or GPCRs. Chemokines are divided into four groups based on the primary sequence of the first two cysteines: the CXC, CC, C, and the newly discovered, CX3C families. The CXC and C families are effective predominantly on neutrophils and lymphocytes, respectively. The CC chemokines are preferentially effective on macrophages, lymphocytes, and eosinophils.
Only about half of the chemokines have been paired to respective receptors. Some appear to bind to more than one receptor. The matching of orphan receptors with the many chemokines is an ongoing process. The matching of the ligands with receptors often provide useful insight into the physiological functions of the individual chemokines.
The genome of the human herpesvirus 8 (HHV8), a gammaherpesvirus linked to the etiology of Kaposi""s sarcoma (KS) [Moore, et al., J. Virol. 70:549-558 (1997)] encodes several chemokine-related proteins including a constitutively active G-protein coupled chemokine receptor (vGPCR) that bind several CC and CXC chemokines and three viral chemokines, vMIP-I, vMIP-II and vMIP-III [Moore, et al., Science 274:1739-1744 (1996); Arvanitakis, Nature 385:347-350 (1997); Nicholas, et al., J. Natl. Cancer Inst. Monogr. 23:79-88 (1998); Nicholas, et al., Nat. Med. 3:287-292 (1997)]. In addition to its association with KS, HHV8 has also been suggested to play a role in the pathology of primary effusion lymphoma (PEL) [Cesarman, et al., Am. J. Pathol. 149:53-57 (1996); Nador, et al., Blood 88:645-656 (1996)]. The virus has also recently been linked to the development of multiple myeloma [Rettig, et al., Science 276:1851-1854 (1997)]. Expression of the HHV8 GPCR in rodent fibroblasts leads to a proliferative phenotype, suggesting a role for this constitutively active chemokine receptor in tumorigenesis [Arvanitakis, et al., Nature 391:86-89 (1998)].
There is a need for understanding the role of these chemokine-related proteins in HHV8 replication and the pathogenesis of HHV8-related disease states, and generally for regimes for the treatment of viral disease and associated pathology.
The present invention fulfills this need by providing materials and methods for treating disease states associated with immune dysfunction. The invention is based upon the surprising discovery that the vMIP-I is an agonist of the chemokine receptor CCR8, a receptor located on activated Th2 cells.
One object of the present invention is to provide a means for modulating the balance of Th1 and Th2 cells in an animal using the vMIP/CCR8 interaction. Such modulation includes increasing and decreasing the level of Th2 cells in order to treat various disease states.
Another object of the present invention provides a new method of treating patients for various immune related disorders and diseases using the vMIP/CCR8 interaction
One aspect of the invention provides a method of modulating a physiological signal specifically to activated Th2 cells. The method comprises contacting activated Th2 cells with vMIP-1, or a vMIP-1 analog or antagonist. The modulating may be blocking,for example, by contacting with a vMIP-I antagonist, e.g., an antibody. Alternatively, the modulating may be inducing with an agonist,such as, by contacting with a CCR8 signaling ligand, e.g., vMIP-I or a vMIP-I signalling analog. The modulating may be directing a response between a Th1 and Th2 response, where the contacting is with vMIP-I, a vMIP-I antagonist or vMIP-I signaling agonist. The physiological signal may be a proliferation, apoptosis, or differentiation signal. The contacting may be in combination with another chemokine or cytokine agonist or antagonist, including IL-12, an IL-12 antagonist, IL-1xcex3, or an IL-1xcex3 antagonist.
Another aspect of the invention provides methods for diagnosing and/or treating a patient infected with a virus comprising utilizing a vMIP-I antagonist, such as, but not limited to, blocking monoclonal antibodies raised against vMIP-I, a modified vMIP-I peptide or a small molecule antagonist for vMIP-I. These entities block the interaction between vMIP-1 and CCR8, or prevent appropriate signaling through CCR8. This, in turn, blocks the skewing of host responses toward a Th2 phenotype thus making treatment of virus-mediated tumors more effective and/or block anti-apoptotic effects of CCR8 again leading to more effective treatment of such tumors. The knowledge of the vMIP-I/CCR8 interaction also makes available as treatments for viral infection other agents that block this interaction. For example, CCR8 antagonists, I-309 (natural ligand) antagonists and other CCR8 ligand antagonists can be used in the same way as a vMIP-I antagonist to block the vMIP-I/CCR8 interaction.
Still another aspect of the invention provides methods for skewing an immune reponse toward a Th2 phenotype, such as, for example in the treatment of auto-immune diseases (principally Th1 in nature) in which skewing to Th2 lessens disease severity and/or improves the performance of a co-therapy, and in the treatment of bacterial/parasite infections, where the immune response is principally Th2 in nature. In the latter case, vMIP-I or signal agonists thereof increases effectiveness of a Th2 response leading to more rapid eradication of these pathogens.